In the developed countries a significant part of deaths is caused by the cardiovascular disorders. These diseases are mostly triggered by the atherosclerotic alteration of the coronary arteries. Among the risk factors for development of the illness as the high blood pressure, diabetes, smoking etc. the most important is the high concentration of cholesterol in the serum. The active ingredients and formulations decreasing concentration of the serum cholesterol are useful agents in treating and preventing atherosclerosis.

Ezetimibe, i.e., 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone of Formula I is the active ingredient of some up-to-date marketed pharmaceutical preparations having significant hypocholesterolemic effect used in the treatment and preventing of atherosclerosis, disclosed in U.S. Pat. No. 5,767,115 (Schering Co. U.S.A.) and European Patent No. 720,599
The first synthetic methods for the preparation of ezetimibe and relatives were published in these descriptions. According to one of their methods the appropriate trans-azetidinone derivative is prepared in one step with the reaction of [4-(benzyloxy)-benzylidene]-(4-fluorophenyl)-amine and methyl-4-(chloro-formyl)-butyrate base, and after hydrolysis and forming an acid chloride with the given 3-[2-(4-benzyl-oxy-phenyl)-1-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl-chloride (4-fluorophenyl)-zinc-chloride is acylated in the presence of tetrakis(triphenyl-phosphine) Palladium. The pure 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)-propyl)]-4(S)-(4-benzyloxy-phenyl)-2-azetidinone is obtained by chiral HPLC separation, that the end-product ezetimibe is prepared from by subsequent enantioselective reduction and cathalytic hydrogenation. In this method the substituted azetidinone ring was not formed by an enantioselective method, therefore the last but one intermediate is purified by a chiral column chromatographic method. In this manner at least 50% of a late intermediate is lost significantly increasing the costs of procedure.
To avoid the costly chiral chromatography a microbiological and an enzymatic separation method were introduced in U.S. Pat. No. 5,919,672 (Schering Co.). Although the microbiological method decreases the costs of resolving of the racemate, but even in this manner the yield of resolvation can not be increased above 50%.
In the European Patent No. 720,599 (Schering Co.) the preparation methods of some tri-substituted azetidinone derivatives having hipocholesterinemic activity are disclosed. For forming of the β-lactame ring a one-step and a two-step method are described and the building-up of the aril-hydroxy-alkyl side-chain is carried out by several methods. For the synthesis of ezetimibe an enantioselective method is revealed. First the azetidinone ring is formed in a two-step synthesis from 5-oxo-5-((S)-2-oxo-4-phenyl-oxazolidine-3-yl)-pentane acid methyl ester and [4-(benzyloxy)-benzylidene]-(4-fluorophenyl)-amine. An acylation is carried out with the aid of the obtained 3-[(2S,3R)-2-(4-benzyl-oxy-phenyl)-1-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl-chloride in the presence of (4-fluorophenyl)-zinc-chloride tetrakis(triphenyl-phosphine)-palladium. The given 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl)]-4(S)-(4-benzyloxy-phenyl)-2-azetidinone intermediate is purified by column chromatography, then the active ingredient is obtained after an enantioselective reduction of the oxo group, and removing of the protecting group.
From the former procedures a strategically different method was published in the International Application No. WO 97/45,406 and in U.S. Pat. No. 5,739,321 (Schering Co). According to these publications enantioselective forming of the trans-substituted azetidinone intermediate is carried out by a reaction of 4(S)-hydroxy-butyrolactone and a protected imine in the presence of a base, then the 3-(4-fluorophenyl)-3-hydroxypropyl side chain is built up in a several-step synthesis through the mentioned 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)-propyl)]-4(S)-(4-benzyloxy-phenyl)-2-azetidinone intermediate. The benzyl protecting group is removed by catalytic hydrogenation.
Another reaction pathway is disclosed in U.S. Pat. No. 5,856,473. (Schering Co.). According to the description (3R,4S)-4-(4-benzyloxy-phenyl)-1-(4-fluorophenyl)-3-[(E)-3-(4-fluorophenyl)-allyl]-azetidin-2-one including a double bond in the side chain is prepared alkylating with 1-(4-fluorophenyl)-4(S)-(4-benzyl-oxy-phenyl)-2-azetidinone 4-fluorocinnamyl-bromide, or with an enantioselective synthesis starting from (S)-3-[5-(4-fluorophenyl)-pent-3-enoil]-4-phenyl-oxazolidine-2-one. 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl)]-4(S)-(4-benzyloxy-phenyl)-2-azetidinone intermediate is obtained with oxydating the side chain, from which the end-product ezetimibe is obtained after removing of the protecting group by the enantioselective reduction mentioned.
These enantioselective procedures are common in the subsequent using of multi-step synthesis methods with the optically pure azetidinone derivatives prepared with the relative costly enantioselective synthesis procedures. The key intermediate, 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl)]-4(S)-(4-benzyloxy-phenyl)-2-azetidinone is purified only by chromatography increasing significantly the costs of the industrial methods.
In the Patent Applications No. WO 2000/34,240 (Schering Co.) and in No. WO 1995108,532 and in the European Patent No. 0,720,599 (Schering Co.) an improved and more effective and enantioselective ezetimibe synthesis pathway is discovered. According to the procedure first 3-[(S)-5-(4-fluorophenyl)-5-hydroxy-pentanoyl]-oxazolidine-2-one is prepared in 98% de (diastereomer excess) purity from the appropriate oxo-compound with an enantioselective reduction. 3-[(S)-5-(4-fluorophenyl)-5-hydroxy-pentanoyl]-oxazolidine-2-one and N-(4-hydroxy-benzylidene)-4-fluoroanilin are silylated in situ with chlorotrimethylsilane in one vessel. The appropriate β-amino-amid product is prepared by treating the obtained mixture with TiCl4 reagent in the presence of a base using a procedure well-known in the art. The authors experienced surprising stability of the trimethylsilyl protecting group of phenolic OH group. In spite of the stability of the silyl group the intermediate could be isolated only with a 65% yield after work-up and further silylation step. Ezetimibe is obtained after cyclisation of the β-amino-amide followed by removing of the protecting groups. In this procedure formation of the 3(S)-hydroxy group with relatively costly enantioselective method is carried out at the beginning of the synthesis then the product is isolated after further reaction steps and purification procedure.
Stereoselective forming of the 3(S)—OH group is one of the key steps preparing ezetimibe. Each of the mentioned procedures applies one of the versions of the enantioselective reduction methods catalysed by CBS-oxazaborolidine, well-known from the literature (E. J. Corey et al., J. Am. Chem. Soc. 1987, 109, 5551-5553). The achieved de-value (diastereomer excess) is 88-98%, as it expected typically.
U.S. Pat. Nos. 5,886,171 and 5,856,473 (Schering Co.) describe an enantoselective reduction method using CBS-oxazaborolidine catalyst, in which the protected 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone is converted to protected 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone.
U.S. Pat. Nos. 6,207,822 and U.S. Pat. No. 6,627,757 (Schering Co.) describe application of similar reducing agents and chiral catalysts for converting of 3-[5-(4-fluorophenyl)-5-oxo-pentanoyl]-4(S)-4-phenyl-1,3-oxazolidine-2-one to 3-[5(S)-5-(4-fluorophenyl)-5-hydroxy-pentanoyl]-4(S)-4-phenyl-1,3-oxazolidine-2-one.
In U.S. Pat. No. 5,618,707 and in Patent Application No. WO 1997/12,053 (Schering Co.) another possibility of enantoselective reduction is described, in which an early intermediate 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-4(S)-4-phenyl-1,3-oxazolidine-2-one is converted by a stereoselective microbiological reduction to 3-[5(S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4(S)-4-phenyl-1,3-oxazolidine-2-one. The achieved de-value≧95% (diastereomeric excess) is similar to that of the value obtained by the CBS-oxazaborolidine catalysis.
In U.S. Pat. No. 6,133,001 a stereoselective microbiological reduction is describe for conversion of 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone into 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone (ezetimibe). The end-product is prepared in a small quantity, and it is purified by preparative thin-layer chromatography.
In the International Application No. WO 2005/066,120 (Ranbaxy Ltd.) the enantioselective reduction of the oxo group of 3-[5-(4-fluorophenyl)-5-oxo-pentanoyl]-4(S)-4-phenyl-1,3-oxazolidine-2-one and of 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone are performed by (−)-B-chloro-diisopinocampheyl-borane achieving a selectivity similar to CBS-reduction. However, it is interesting that in this manner in the reduction of 20 g 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone as little as 3 g ezetimibe end-product is obtained after a column-chromatographic purification.